Behavioural evaluation of cholinergic drugs.

Alzheimer's disease involves progressive degeneration of the cortex and the limbic system. Loss of afferent forebrain neurochemical modulatory systems is also seen, most significantly of the basal forebrain cholinergic system. Drug discovery programmes have pursued enhancement of forebrain muscarinic function as a therapeutic target. The most promising muscarinic agonists described achieve functional selectivity as agonists as the M1/M3 receptors in the CNS and M2 antagonists. These compounds have fewer cardiac and other cholinergic side effects. In rodent and monkey models of reference and working memory, these compounds reverse the cognitive impairment induced with plopolamine. Acetylcholinesterase inhibitors are even more efficacious in these models.